This application is in response to RFA DA-09-016, "Behavioral Pharmacology and Genetics, Translating and Targeting Individual Differences." The proposed project will examine the genetic basis of individual differences in inhibitory control (IC) and how these factors interact to increase severity of abstinence-induced smoking withdrawal and subsequent smoking reinforcement. This work will systematically extend work conducted by the investigative team showing that 1) genetic variation in the DRD2 gene is associated with differential levels of IC;2) smoking abstinence causes significant disruptions in IC;and 3) IC predicts smoking severity and propensity to relapse following a period of abstinence. One hundred adult smokers will be enrolled and baseline levels of IC will be assessed using commission errors from a continuous performance test (CPT). All subjects will be genotyped and will undergo biochemically verified 24-hour abstinence. IC will again be assessed using the CPT, as well as smoking reinforcement using a progressive ratio (PR) task. We predict that individuals with specific genotypes of the DRD2 gene will exhibit more commission errors (i.e., worse IC) compared to individuals with alternative genotypes. We also predict that smoking-abstinence induced disruptions in IC will be associated with smoking reinforcement and that this association will be moderated by DRD2 genotype. This work is significant since it will help identify genetically-influenced individual differences that significantly predict aspects of smoking withdrawal and reinforcement (and hence, subsequent risk for relapse). The proposed experiment will also provide the basis for a wide range of hypothesis-generating exploratory analyses. PUBLIC HEALTH RELEVANCE: Individuals who have difficulty inhibiting appropriate responding on a range of tasks are at risk for a number of substance abuse outcomes, including cigarette smoking. Also, these inhibitory control problems may be more pronounced during smoking abstinence, which may increase the risk for relapse. This project will help identify specific genes that are associated with inhibitory control and determine how both genes and IC are related to smoking withdrawal and risk for relapse. This work will have significant public health implications by determining those individuals who are at highest risk for smoking relapse following a quit attempt.